Antimicrobial resistance, which entails the microorganisms ability to find ways aimed at circumventing the actions of the drugs used to cure the infections caused by such microorganisms, is held as a current public health issue not only because of the growing trend of resistant bacteria, but also due to the lack of new antibiotics [ECDC/EMEA Joint Technical Report; The bacterial challenge: time to react. A call to narrow the gap between multidrug-resistant bacteria in the EU and the development of new antibacterial agents; September 2009].
Back in 2004, the World Health Organization (WHO) initially envisaged a future lacking effective antibiotics and asserted that resistance to antibiotics is one of three most serious threats to all mankind. [W. Kaplan, R. Laing, Priority Medicines for Europe and the World; World Health Organization; Department of Essential Drugs and Medicines Policy, November 2004]. In turn, there is a growing demand of antibiotics not only due to the resistance issue, but also to the extended life expectancy of the population, a higher infection rate and an increasing number of immunocompromised patients.
According to the WHO, deaths caused by acute respiratory infections, diarrheas, measles, HIV, malaria and tuberculosis account for 85% of mortality due to infections. Resistance against first-line treatment drugs for the majority of these pathogens giving rise to the above mentioned diseases ranges from 0 to 100%. Additionally, resistance has been found to occur with second or third-line treatment drugs, which therefore exerts an impact on these diseases therapy. Furthermore, importance is to be attached to resistance emerging from intrahospital infections strains. People's growing inter-country mobility rate not only has increased the spread of infectious diseases but also the risk of resistance. Not only does resistance affect people's quality of life, but it also claims their lives, entails Public Health Institutions monetary investments in various countries, and results in healthcare plans proving inefficient and uncertain.
Multi-drug resistant Gram-positive bacteria (MDRGP) still continue to pose challenges to the scientific community, which involve both Staphylococcus aureus, whose first penicillin-resistant strains emerged in the 50's and recent cases such as penicillin-resistant Streptococcus pneumoniae and Mycobacterium tuberculosis-resistant strains (specifically involving acid-resistant Gram-positive bacteria). It is worth highlighting that roughly 500,000 patients are yearly diagnosed with multiple-drug resistant tuberculosis and 110,000 of them encounter death. The multiple-drug resistant Gram-negative bacteria (MDRGN) have turned into an issue of concern over the last years, particularly, the E. coli-resistant strains.
Antimicrobial resistance also poses a threat to further healthcare breakthroughs over the last years. Thus, co-infections with HIV and resistant pathogens, tuberculosis, salmonellosis and other sexually transmitted diseases may feature a rapidly-advancing spread and progression and a potential multiplier effect on resistance transmission. A disease like tuberculosis, which had become completely treatable and controllable, has turned into a menace over again. 3.6% of the worldwide occurring tuberculosis cases have proved resistant to the regularly administered antibiotics.
Therefore, the search for new chemical entities with antimicrobial properties and structures differing from those found in conventional antibiotics is viewed as a pressing need to develop new ways to curb these resistant infections. The caffeic acid (3,4-dihydroxycinnamic acid) and its esters, are phenolic compounds widely distributed in the plant kingdom. The majority of these compounds feature antibacterial, antiviral, anti-sclerotic, anti-HIV and anti-tumor activities, among others. The caffeic acid structure also makes up the central core of hygromycin A, a broad-spectrum antibiotic obtained from Streptomyces hygroscopicus [R. C. Pittenger, R. N. Wolfe, P. N. Hoehn, W. A. Daily, J. M. McGuire, Antibiot. Chemother., 3 (1953) 1268-1278]. Results from various recently developed investigations involving the testing of simple caffeic amides and related compounds with significant antibacterial activity against Mycobacterium tuberculosis resistant strains [G. K. Yoya, F. Bedos-Belval, P. Coonstant, H. Durán, M. Daffé, M. Baltas, Bioorg. Med. Chem. Lett., 18 (2008) 538-541; J. Fu, K. Cheng, Z-M. Zhang, R-Q. Fang, H-L. Zhu, Eur. J. Med. Chem., 45 (2010) 2638-2643] and Staphilococcus aureus [R. J. Herr, Bioorg. Med. Chem., 10 (2002) 3379-3393; B.-e. Yingyongnarongkul, N. Apiratikul, N. Aroonrerk, A. Suksamram, Bioorg. Med. Chem. Lett., 16 (2006) 5870-5873], are currently available. Some of the

Its simple structure and the ease with which functional and structural changes may be carried out, make caffeic acid an ideal scaffold to develop new families of compounds.
Biological activity studies have shown certain structural characteristics that are to be found in the caffeic acid active derivatives; particularly, the unprotected phenolic hydroxyls at positions 3 and 4 of the aromatic ring that provide the redox couple responsible for their antioxidant activity, and the carboxyl group forming amides with aliphatic or aromatic amines in the specific case of antibacterial activity.